Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor
| Autor: | Kristýna Krasulová, Karolína Poulíková, Peter Illes, Radim Vrzal, Zdeněk Dvořák, Barbora Vyhlídalová, Petra Pečinková, Natália Sirotová, Sridhar Mani, Adéla Marcalíková |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male ATP Binding Cassette Transporter Subfamily B Indoles Context (language use) Toxicology Ligands Transfection digestive system 03 medical and health sciences 0302 clinical medicine Genes Reporter Cell Line Tumor Cytochrome P-450 CYP3A Humans Intestinal Mucosa Receptor Cells Cultured Indole test Pregnane X receptor Reporter gene CYP3A4 Indoleacetic Acids Chemistry Tryptophan Pregnane X Receptor General Medicine digestive system diseases Gastrointestinal Microbiome 030104 developmental biology Biochemistry Chromatin immunoprecipitation 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Toxicology letters. 334 |
| ISSN: | 1879-3169 |
| Popis: | The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 μM) and IAD (IC50 10 μM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry. |
| Databáze: | OpenAIRE |
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